Stem cells are defined as multipotent, self-renewing undifferentiated cells capable of differentiating into numerous cell lineages. A great deal of interest has focused on the potential therapeutic application of such stem cell populations, not only to repair or replace damaged tissues, but as model systems to understand basic developmental processes leading to normal and abnormal cellular development. As a result, this application requests support from the IDeA program to establish a COBRE in Stem Cell Biology and Regenerative Medicine and involves the collaborative interests of a group of four (non-RO1 funded) junior investigators, including 1 from The Jackson Laboratory, under the mentorship of an established investigator in the field of Stem Cell Biology within the Center for Regenerative Medicine at the Maine Medical Center. The intent of including The Jackson Laboratory is to establish and bridge long-term collaborative research programs in the state of Maine. The theme of the application involves investigations into the signals, receptors, signaling cascades, and transcriptional regulatory circuits that control stem cell development. The motives for this application include the use of this award to (i) support, develop, and advance promising young investigators in the field of Stem Cell Biology, (ii) expand existing institutional resources to create a critical mass of mechanism-oriented junior and senior investigators in this area, (iii) establish and expand core resources in Stem Cell Isolation, Pathology, and Molecular Genetics to support ongoing and future investigator needs, and (iv) provide resources requisite for the establishment of an internationally recognized non-profit research institution in the broad area of Stem Cell Biology, with the potential to ultimately apply this information to the field of Regenerative Medicine. The application is comprised of four projects that were chosen in the field of Stem Cell Biology and are the crux of current investigations in the field. These projects include (i) The role of pMesogenin in the mesodermal differentiation of embryonic stem cells, (ii) Notch signaling events in the self-renewal of embryonic stem cells, (iii) The role of Wnt signaling in the preimplantation embryo, and (iv) VEGFR-Notch-Prox resolution of lymph vessel fate. Program expansion beginning in 2003 will include the recruitment of at least 5 investigators with genetic, cellular, and molecular expertise to address mechanistic questions in the general areas of (i) stem cell plasticity, (ii) Hedgehog signaling events in lineage specification, (iii) computational biology, (iv) non-murine models of development, (v) transplantation biology, and (vi) genomics, proteomics, and systems biology. It is anticipated that this award will not only enable the Center for Regenerative Medicine to achieve its goal at a more rapid and efficient rate, but the insight derived from these investigations may significantly impact the field of Stem Cell Biology and Regenerative Medicine.